A5082192456- RNA Interference and Gene Delivery
- Advanced biosensing and bioanalysis techniques
- Virus-based gene therapy research
- DNA and Nucleic Acid Chemistry
- Viral Infections and Outbreaks Research
- Viral Infections and Vectors
- Viral gastroenteritis research and epidemiology
- Pharmacogenetics and Drug Metabolism
- RNA Research and Splicing
- Muscle Physiology and Disorders
- Coronary Interventions and Diagnostics
- Animal Virus Infections Studies
- Trace Elements in Health
- RNA and protein synthesis mechanisms
- Cancer-related Molecular Pathways
- Mosquito-borne diseases and control
- CRISPR and Genetic Engineering
- RNA modifications and cancer
- Acute Myeloid Leukemia Research
- HIV Research and Treatment
- Drug Transport and Resistance Mechanisms
- Bacteriophages and microbial interactions
- DNA Repair Mechanisms
- SARS-CoV-2 and COVID-19 Research
- Viral Infections and Immunology Research
Oregon Health & Science University
2004-2024
Oregon State University
2013-2024
United States Army Medical Research Institute of Infectious Diseases
2006-2023
The Geneva Foundation
2021-2023
United States Army
2023
Sarepta Therapeutics (United States)
2008-2017
Duke Medical Center
2009
Old Dominion University
2008
Experimental Station
2008
National Institutes of Health
2008
Cell-penetrating peptides (CPPs), containing arginine (R), 6-aminohexanoic acid (X), and/or β-alanine (B) conjugated to phosphorodiamidate morpholino oligomers (PMOs), enhance their delivery in cell culture. In this study, the potency, functional biodistribution, and toxicity of these conjugates were evaluated vivo, EGFP-654 transgenic mice that ubiquitously express aberrantly spliced pre-mRNA reporter. Correct splicing enhanced green fluorescence protein (EGFP) upregulation serve as a...
Antisense oligonucleotide-mediated exon skipping is able to correct out-of-frame mutations in Duchenne muscular dystrophy and restore truncated yet functional dystrophins. However, its application limited by low potency inefficiency systemic delivery, especially failure dystrophin heart. Here, we conjugate a phosphorodiamidate morpholino oligomer with designed cell-penetrating peptide (PPMO) targeting mutated exon. Systemic delivery of the novel PPMO restores almost normal levels cardiac...
Although the sequence specificity, biostability, and low toxicity of PMO (phosphorodiamidate morpholino oligomers) make them good antisense agents to study gene function, their limited ability cross cell membranes limits use in culture. In this paper we show that conjugation arginine-rich peptides significantly enhanced cellular uptake PMO. The factors affect conjugate's its activity toward a targeted mRNA were investigated. Factors studied include number arginines peptide, choice...
Objective: Conjugation of arginine-rich cell-penetrating peptide (CPP) to phosphorodiamidate morpholino oligomers (PMO) has been shown enhance cytosolic and nuclear delivery PMO. However, the in vivo disposition CPP−PMO is largely unknown. In this study, we investigated pharmacokinetics, tissue distribution, stability, safety profile an anti-c-myc PMO conjugated CPP, (RXR)4 (X = 6-aminohexanoic acid) rats. Methods: The were administrated intravenously into concentrations plasma tissues...
Cell penetrating peptides (CPPs) have been shown to enhance the cellular uptake of antisense oligonucleotides (AOs). However, effectiveness CPPs for cytoplasmic or nuclear delivery therapeutic AOs must take into account possible entrapment CPP-AO conjugates in endosomes/lysosomes and overall stability enzymes. This includes stabilities themselves as well linkage between them. In this study, we investigated effects several structural features arginine-rich on metabolic CPP conjugated...
When injected into SCID mice, the Philadelphia chromosome-positive chronic myeloid leukemia-blast crisis cell line BV173 induces a disease process closely resembling that seen in leukemia patients. At 1 and 3 weeks after injection of 10(6) cells, CD10+ cells were detected bone marrow leukemic colonies grew from spleen suspensions, BCR-ABL transcripts detectable marrow, spleen, peripheral blood, liver, lungs. Systemic treatment mice with 26-mer antisense oligodeoxynucleotide (1 mg/day for 9...
Duchenne and Becker muscular dystrophies are allelic disorders arising from mutations in the dystrophin gene. dystrophy is characterized by an absence of functional protein, whereas dystrophy, commonly caused in-frame deletions, shows synthesis partially protein. Anti-sense oligonucleotides can induce specific exon removal during processing primary transcript, while maintaining or restoring reading frame, thereby overcome protein-truncating mutations. The mdx mouse has a non-sense mutation...
There are no currently approved treatments for filovirus infections. In this study we report the discovery process which led to development of antisense Phosphorodiamidate Morpholino Oligomers (PMOs) AVI-6002 (composed AVI-7357 and AVI-7539) AVI-6003 AVI-7287 AVI-7288) targeting Ebola virus Marburg respectively. The involved identification optimal transcript binding sites PMO based RNA-therapeutics followed by screening effective viral gene target in mouse guinea pig models utilizing adapted...
Significance Duchenne muscular dystrophy (DMD) is a lethal genetic disorder caused by lack of dystrophin protein. Cardiomyopathy leading cause death in DMD. Although exon skipping with antisense morpholino oligonucleotides very promising, morpholino-mediated has induced barely detectable levels the hearts DMD animal models. Here, we show that systemic multiexon using cocktail peptide-conjugated morpholinos (PPMOs) rescued expression myocardium and cardiac Purkinje fibers dystrophic dog...
Abstract Remdesivir (GS-5734; VEKLURY) is a single diastereomer monophosphoramidate prodrug of an adenosine analog (GS-441524). taken up by target cells and metabolized in multiple steps to form the active nucleoside triphosphate (GS-443902), which acts as potent inhibitor viral RNA-dependent RNA polymerases. GS-441524 have antiviral activity against viruses. Here, we expand evaluation remdesivir’s members families Flaviviridae , Picornaviridae Filoviridae Orthomyxoviridae Hepadnaviridae....
RNA elements within flavivirus genomes are potential targets for antiviral therapy. A panel of phosphorodiamidate morpholino oligomers (PMOs), whose sequences complementary to located in the 5'- and 3'-termini West Nile (WN) virus genome, were designed anneal important cis-acting potentially inhibit WN infection. novel Arg-rich peptide was conjugated each PMO efficient cellular delivery. These PMOs exhibited various degrees activity upon incubation with a luciferase-replicon-containing cell...
Androgen-insensitive prostate cancer cells are highly resistant to several chemotherapeutic drugs and characterized by the appearance of apoptosis-resistant cells. In this study, we identified critical role X-linked inhibitor apoptosis protein (XIAP), a potent antiapoptotic factor, in conferring chemotherapy resistance an androgen-insensitive DU145 human cell line. Results reveal that were cisplatin, but was overridden when treated for prolonged time (>96 hours) with cisplatin (IC(50) = 27.5...
The filoviruses Marburg virus and Ebola (EBOV) quickly outpace host immune responses cause hemorrhagic fever, resulting in case fatality rates as high 90% humans nearly 100% nonhuman primates. development of an effective therapeutic for EBOV is a daunting public health challenge hampered by paucity knowledge regarding filovirus pathogenesis. This report describes successful strategy interfering with infection using antisense phosphorodiamidate morpholino oligomers (PMOs). A combination...
A synthetic phosphorothioate oligonucleotide was administered systemically to five patients with either relapsed or refractory acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS). Patients received a 10-day continuous intravenous infusion of this compound, which is complementary p53 mRNA. No major toxicity attributable dose 0.05 mg/kg/hr observed. range approximately 9 18% the recovered in urine as intact oligonucleotide. Evaluation malignant cells from bone marrow and...
PURPOSE The phosphoprotein p53 is involved in transcriptional regulation and detected hematologic malignancies. In vitro incubation of acute myelogenous leukemia with OL(1)p53, a 20-mer phosphorothioate oligonucleotide complementary to mRNA, results leukemic cell death. A phase I dose-escalating trial was conducted determine the toxicity OL(1)p53 following systemic administration patients PATIENTS AND METHODS Sixteen either refractory (n = 6) or advanced myelodysplastic syndrome 10)...